ShcA is an integrator of ErbB2 and TGFÃ signaling pathway interactions in Breast Cancer
Bibliographic record
Abstract
The ErbB2 and TGFβ signaling pathways cooperate to promote breast cancer progression and metastasis. The formation of distant metastases is the leading cause of mortality for breast cancer patients. To identify the mechanisms underlying the synergy between ErbB2 and TGFβ pathways, we transformed mammary epithelial cells with a panel of activated ErbB2 receptors, in which specific autophosphorylation sites that initiate distinct signaling pathways were mutated. We determined tyrosine residues 1226/1227 and 1253 within the ErbB2 receptor are required for TGFβ-induced migration and invasion of breast cancer cells. Using transient knockdown approaches, we subsequently demonstrated that ShcA was required downstream of these tyrosine residues for these TGFβ-mediated effects. In addition, TGFβ stimulation of ErbB2-expressing breast cancer cells with diminished ShcA expression resulted in the formation of larger and more numerous focal adhesions. These results indicated that signaling through ShcA is required for the TGFβ-induced formation of pro-migratory, dynamic focal adhesions in ErbB2-expressing cells. To investigate a requirement for ShcA signaling in the promotion of tumor progression and metastasis in vivo, we generated ErbB2-expressing breast cancer cells with a stable shRNA-mediated knockdown of ShcA expression. Diminished ShcA expression impaired tumor growth and spontaneous metastasis. Immunohistochemical staining revealed that loss of ShcA signaling results in decreased tumor proliferation and endothelial cell recruitment, coupled with an increase in apoptosis. Rescue experiments with wild-type ShcA or a panel of ShcA functional domain mutants revealed that the PTB-domain and three tyrosine residues (239/240 and 313) were necessary for TGFβ-induced migration and invasion. The Grb2 and Crk adaptor proteins have been implicated in signaling downstream of these ShcA tyrosine residues. A transient knockdown of these adaptors uncovered specific roles for Grb2 downstream of ShcA Y313 and the Crk adaptors downstream of ShcA Y239/240 for TGFβ-induced effects. An investigation of the significance of these ShcA tyrosine sites for tumor growth in vivo demonstrated that ShcA signaling through Y313 enhances tumor cell survival while signaling through ShcA Y239/240 promotes the recruitment of endothelial cells. Finally, we employed an inducible knockdown of ShcA to identify acute TGFβ-induced gene expression changes in ErbB2-expressing cells that depend on ShcA expression. We identified numerous candidate genes that were regulated by TGFβ in a ShcA-dependent manner, including the BMP antagonist, Chordin-like 1. We confirmed that reduced ShcA signaling results in the up-regulation of secreted Chordin-like 1 protein in ErbB2-expressing cells following TGFβ stimulation. Functional roles for Chordin-like 1 in ErbB2-driven tumor growth, survival and angiogenesis are currently being investigated.The work described in this thesis is the first to identify ShcA as an integral mediator underlying the cooperation between the ErbB2 and TGFβ signaling pathways in breast cancer progression and to define molecular mechanisms through which ShcA functions in this context.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".